Despite viral vectors’ predominant use in clinical trials, due to higher gene delivery efficiency than nonviral counterparts, intrinsic immunogenicity and limited tunability for multi-modal effects are major concerns for their usage in gene therapy. An adeno-associated viral (AAV) particle was shielded with acid-degradable, siRNA-encapsulating polyketal (PK) shell, resulting in core–shell viral/nonviral chimeric nanoparticles (ChNPs). The AAV core of a ChNP is protected from immune responses by the PK shell which also facilitates the intracellular trafficking of the AAV core and efficiently releases the encapsulated siRNA into the cytoplasm. ChNPs led to significantly enhanced gene transduction, compared to unmodified free AAVs, and simultaneous silencing of a target gene, while avoiding inactivation by recognition from the immune system. Furthermore, conjugation of sialic acid (SA) on the surface of ChNPs enabled receptor-mediated targeted gene delivery to CD22-expressing cells. The ChNPs developed in this study combine the advantages of both viral and nonviral vectors and are a promising platform for targeted co-delivery of DNA and siRNA in inducing synergistic therapeutic effects by simultaneous expression and silencing of multiple genes.